In Silico Screening of Available Drugs Targeting Non-Small Cell Lung Cancer Targets: A Drug Repurposing Approach

Area of Science:

• Oncology
• Computational Chemistry
• Drug Discovery

Background:

• The RAS-RAF-MEK-ERK pathway is crucial in tumor progression, but upstream kinase complexity hinders treatment.
• MEK inhibition is a viable strategy, yet drug resistance remains a significant challenge in cancer therapy.

Purpose of the Study:

• To discover novel dual-targeting therapeutic agents to overcome MEK inhibitor resistance in cancer.
• To identify compounds with potent activity against both MEK and a co-target using high-throughput virtual screening.

Main Methods:

• Conducted high-throughput virtual screening of 11,808 DrugBank molecules against MEK.
• Employed Glide docking, MLSF, and prime-MM/GBSA methods for lead compound identification.
• Utilized SIE-based free energy calculations to analyze binding interactions.

Main Results:

• Identified two lead compounds, DB012661 and DB07642, with strong in silico activity against MEK.
• Demonstrated significant binding capabilities of these compounds with the co-target PIM1.
• Revealed that van der Waals interactions are key to the binding efficacy with the MEK receptor.

Conclusions:

• The identified compounds, DB012661 and DB07642, show therapeutic potential as dual MEK/PIM1 inhibitors.
• This dual-targeting approach could offer a promising strategy to overcome drug resistance in cancer treatment.
• Further in silico analysis suggests these compounds could be valuable for future drug development against resistant cancers.